Biomarkers of Liver and Gallbladder Function: GGT

Optimal Takeaways

Gamma-glutamyl transferase (GGT) is an enzyme primarily involved in producing and recycling glutathione, a vital antioxidant compound produced in the body. Elevated levels of GGT are associated with oxidative stress, toxin exposure, antioxidant insufficiency, increased glutathione need, hepatobiliary disease, especially cholestasis, and increased risk of cardiometabolic disorders and dementia. Low levels may be associated with nutrient deficiency or the use of certain medications.

Standard Range: 3.00 - 85.00 IU/L

The ODX Range: 10.00 - 17.00 IU/L

Low GGT levels may be associated with magnesium insufficiency (Noland 2020) and vitamin B6 insufficiency (Thomas 1998). Drugs that decrease GGT include oral contraceptives and clofibrate (Pagana 2021).

High GGT levels can be seen with gallbladder disorders, jaundice, hepatic necrosis, cirrhosis, hepatic tumor, myocardial infarction, alcohol intake, pancreatitis, pancreatic cancer, infectious mononucleosis (Epstein-Barr viral infection), and Reye syndrome. Drugs that increase GGT include alcohol, phenobarbital, and phenytoin (Pagana 2021).

Elevated GGT indicates insufficiency of antioxidants and increased oxidative stress and is associated with an increased need for glutathione, systemic inflammation, increased CVD risk, arrhythmias, hypertension, NAFLD (Ndrepepa 2016), dementia (Lee 2020), impaired glucose tolerance, metabolic syndrome (Yousefzadeh 2012, Xu 2011), and exposure to environmental toxins such as heavy metals, polycyclic aromatic hydrocarbons, dioxins, and organochlorine pesticides (Koenig 2015).

Overview

Gamma-glutamyl transferase (GGT) is an important metabolic enzyme whose primary function is maintaining intracellular and extracellular concentrations of the tripeptide antioxidant compound glutathione. The GGT found on cell membranes cleaves extracellular glutathione to provide the amino acids needed to produce glutathione within the cell and vice versa. Elevations in circulating GGT indicate increased oxidative stress, insufficient antioxidant availability, and increased need for glutathione. Increased levels are associated with CVD risk, coronary heart disease, cardiac arrhythmias, arterial hypertension, heart failure, CVD-related mortality, and all-cause mortality. Higher levels are commonly seen in CVD comorbidities, including NAFLD, alcohol intake, metabolic syndrome, insulin resistance, and systemic inflammation, and may even predict these disorders. Glutathione also plays a vital role in redox signaling; cellular proliferation and apoptosis; fibrogenesis; metabolism of nitric oxide, glutamine, and sulfur; storage and transport of cysteine; and detoxification of xenobiotics (Ndrepepa 2016).

GGT is considered the most sensitive enzyme in identifying cholecystitis, cholangitis, or biliary obstruction and can accurately detect even subtle degrees of cholestasis. Increases in GGT are often paralleled by alkaline phosphatase in hepatobiliary disorders but not in bone disorders. Therefore, an elevation of ALP without an elevation in GGT is likely associated with skeletal disease, while an elevation in both likely indicates hepatobiliary disease. Elevations in GGT are common with increased alcohol intake and are seen in 75% of those who drink chronically (Pagana 2021).

Levels of GGT within the standard range but above optimal have been closely associated with metabolic dysfunction, including levels above 16.5 IU/L related to metabolic syndrome and above 20 IU/L with impaired glucose tolerance (Yousefzadeh 2012). Levels above 18 IU/L have been associated with insulin resistance, prehypertension, and cancer (Ryoo 2014, Chun 2013, Van Hemelrijck 1990). In one study, the lowest quintile of GGT, i.e., below 24.5 IU/L (not further categorized), was associated with lower fasting glucose of 85 mg/dL (4.7 mmol/L), fasting insulin of 3.8 uU/L (26.39 pmol/L), LDL cholesterol of 114.1 mg/dL(2.96 mmol/L), and triglycerides of 94 mg/dL (1.06 mmol/L), as well as a higher HDL cholesterol of 56.7 mg/dL (1.47 mmol/L) (Bradley 2013).

Higher GGT, still within the  standard range, was associated with cardiovascular incidents and complications. A prospective study of 6,997 men free of CVD or diabetes at baseline found that a GGT of 22 IU/L or above was significantly associated with fatal coronary heart disease and stroke, especially in those younger than 55. Researchers note that previous studies had linked GGT above 18 IU/L with increased CVD mortality (Wannamethee 2008).

Higher GGT, though within the conventional lab range, was associated with dementia (vascular, Alzheimer’s, and all-cause) in a retrospective longitudinal study of more than 6 million Korean individuals aged 40 and older without dementia at baseline. The highest incidence of dementia was in those with GGT above 22 IU/L, especially in those with increased variability in GGT values. Higher GGT variability was associated with smoking; alcohol intake; higher BMI, waist circumference, blood pressure, fasting glucose, and triglycerides; and greater prevalence of diabetes, hypertension, dyslipidemia, heart failure, MI, and stroke (Lee 2020).

Increased circulating GGT is associated with exposure to environmental toxins such as heavy metals, polycyclic aromatic hydrocarbons, dioxins, and organochlorine pesticides. The degree of exposure should be evaluated as part of a comprehensive workup (Koenig 2015). Increased need for glutathione will trigger the recycling of oxidized glutathione to provide cysteine for de novo synthesis of reduced glutathione, a reaction catalyzed by GGT (Pizzorno 2014).

Researchers postulate that GGT may become a pro-oxidant, particularly in the presence of iron or copper. These metal-based nutrients may be released from red blood cells during GGT elevation, creating a perpetual oxidative chain reaction (Koenig 2015) though further research into this concept is needed (Kunutsor 2016, Neuman 2020).  

References

Bradley, Ryan et al. “Associations between total serum GGT activity and metabolic risk: MESA.” Biomarkers in medicine vol. 7,5 (2013): 709-21. doi:10.2217/bmm.13.71

Chun, Hyejin et al. “Association of serum γ-glutamyltransferase level and incident prehypertension in Korean men.” Journal of Korean medical science vol. 28,11 (2013): 1603-8. doi:10.3346/jkms.2013.28.11.1603

Koenig, Gerald, and` Stephanie Seneff. “Gamma-Glutamyltransferase: A Predictive Biomarker of Cellular Antioxidant Inadequacy and Disease Risk.” Disease markers vol. 2015 (2015): 818570. doi:10.1155/2015/818570

Kunutsor, Setor K. “Gamma-glutamyltransferase-friend or foe within?.” Liver international : official journal of the International Association for the Study of the Liver vol. 36,12 (2016): 1723-1734. doi:10.1111/liv.13221

Lee, You-Bin et al. “Gamma-glutamyl transferase variability and risk of dementia: A nationwide study.” International journal of geriatric psychiatry vol. 35,10 (2020): 1105-1114. doi:10.1002/gps.5332

Ndrepepa, Gjin, and Adnan Kastrati. “Gamma-glutamyl transferase and cardiovascular disease.” Annals of translational medicine vol. 4,24 (2016): 481. doi:10.21037/atm.2016.12.27

Neuman, Manuela G et al. “Gamma glutamyl transferase - an underestimated marker for cardiovascular disease and the metabolic syndrome.” Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques vol. 23,1 (2020): 65-74. doi:10.18433/jpps30923

Noland, Diana, Jeanne A. Drisko, and Leigh Wagner, eds. Integrative and functional medical nutrition therapy: principles and practices. Springer Nature, 2020.

Pagana, Kathleen Deska, et al. Mosby's Diagnostic and Laboratory Test Reference. 15th ed., Mosby, 2021.

Pizzorno, Joseph. “Glutathione!.” Integrative medicine (Encinitas, Calif.) vol. 13,1 (2014): 8-12.

Ryoo, J H et al. “Clinical association between serum γ-glutamyltransferase levels and the development of insulin resistance in Korean men: a 5-year follow-up study.” Diabetic medicine : a journal of the British Diabetic Association vol. 31,4 (2014): 455-61. doi:10.1111/dme.12315

Thapa, P B et al. “Serum gamma glutamyl transferase and alkaline phosphatase in acute cholecystitis.” Journal of Nepal Health Research Council vol. 8,2 (2010): 78-81.

Thomas, L. (Ed.). (1998). Clinical laboratory diagnostics: use and assessment of clinical laboratory results. TH-books Verlagsgesellschaft.

Van Hemelrijck, Mieke et al. “Gamma-glutamyltransferase and risk of cancer in a cohort of 545,460 persons - the Swedish AMORIS study.” European journal of cancer (Oxford, England : 1990) vol. 47,13 (2011): 2033-41. doi:10.1016/j.ejca.2011.03.010

Wannamethee, S G et al. “The value of gamma-glutamyltransferase in cardiovascular risk prediction in men without diagnosed cardiovascular disease or diabetes.” Atherosclerosis vol. 201,1 (2008): 168-75. doi:10.1016/j.atherosclerosis.2008.01.019

Xu, Yu et al. “Cross-sectional and longitudinal association of serum alanine aminotransaminase and γ-glutamyltransferase with metabolic syndrome in middle-aged and elderly Chinese people.” Journal of diabetes vol. 3,1 (2011): 38-47. doi:10.1111/j.1753-0407.2010.00111.x

Yousefzadeh, Gholamreza et al. “Role of gamma-glutamyl transferase (GGT) in diagnosis of impaired glucose tolerance and metabolic syndrome: a prospective cohort research from the Kerman Coronary Artery Disease Risk Study (KERCADRS).” Diabetes & metabolic syndrome vol. 6,4 (2012): 190-4. doi:10.1016/j.dsx.2012.08.013